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Eva Morava - One of the best experts on this subject based on the ideXlab platform.
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D-galactose supplementation in individuals with PMM2-CDG: results of a multicenter, open label, prospective pilot clinical trial.
Orphanet journal of rare diseases, 2021Co-Authors: Peter Witters, Jaak Jaeken, David Cassiman, Hans Andersson, Laura Tseng, Clara D M Van Karnebeek, Dirk J Lefeber, Eva MoravaAbstract:PMM2-CDG is the most prevalent congenital disorder of glycosylation (CDG) with only symptomatic therapy. Some CDG have been successfully treated with D-galactose. We performed an open-label pilot trial with D-galactose in 9 PMM2-CDG patients. Overall, there was no significant improvement but some milder patients did show positive clinical changes; also there was a trend toward improved glycosylation. Larger placebo-controlled studies are required to determine whether D-galactose could be used as supportive treatment in PMM2-CDG patients.Trial registration ClinicalTrials.gov Identifier: NCT02955264. Registered 4 November 2016, https://clinicaltrials.gov/ct2/show/NCT02955264.
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Spontaneous improvement of carbohydrate-deficient transferrin in PMM2-CDG without mannose observed in CDG natural history study.
Orphanet journal of rare diseases, 2021Co-Authors: Peter Witters, Hudson H. Freeze, Andrew C. Edmondson, Christina Lam, Christin Johnsen, Marc C. Patterson, Kimiyo Raymond, Eva MoravaAbstract:A recent report on long-term dietary mannose supplementation in phosphomannomutase 2 deficiency (PMM2-CDG) claimed improved glycosylation and called for double-blind randomized study of the dietary supplement in PMM2-CDG patients. A lack of efficacy of short-term mannose supplementation in multiple prior reports challenge this study's conclusions. Additionally, some CDG types have previously been reported to demonstrate spontaneous improvement in glycosylated biomarkers, including transferrin. We have likewise observed improvements in transferrin glycosylation without mannose supplementation. This observation questions the reliability of transferrin as a therapeutic outcome measure in clinical trials for PMM2-CDG. We are concerned that renewed focus on mannose therapy in PMM2-CDG will detract from clinical trials of more promising therapies. Approaches to increase efficiency of clinical trials and ultimately improve patients' lives requires prospective natural history studies and identification of reliable biomarkers linked to clinical outcomes in CDG. Collaborations with patients and families are essential to identifying meaningful study outcomes.
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PMM2-CDG caused by uniparental disomy: Case report and literature review.
JIMD reports, 2020Co-Authors: Laurien Vaes, Belén Pérez, George E. Tiller, Suzanne Boyer, Susan A. Berry, Kyriakie Sarafoglou, Eva MoravaAbstract:Background Phosphomannomutase 2 deficiency (PMM2-CDG) affects glycosylation pathways such as the N-glycosylation pathway, resulting in loss of function of multiple proteins. This disorder causes multisystem involvement with a high variability among patients. PMM2-CDG is an autosomal recessive disorder, which can be caused by inheriting two pathogenic variants, de novo mutations or uniparental disomy. Case presentation Our patient presented with multisystem symptoms at an early age including developmental delay, ataxia, and seizures. No diagnosis was obtained till the age of 31 years, when genetic testing was reinitiated. The patient was diagnosed with a complete maternal mixed hetero/isodisomy of chromosome 16, with a homozygous pathogenic PMM2 variant (p.Phe119Leu) causing PMM2-CDG.A literature review revealed eight cases of uniparental disomy as an underlying cause of CDG, four of which are PMM2-CDG. Conclusion Since the incidence of homozygosity for PMM2 variants is rare, we suggest further investigations for every homozygous PMM2-CDG patient where the segregation does not fit. These investigations include testing for UPD or a deletion in one of the two alleles, as this will have an impact on recurrence risk in genetic counseling.
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repurposing the aldose reductase inhibitor and diabetic neuropathy drug epalrestat for the congenital disorder of glycosylation PMM2 cdg
Disease Models & Mechanisms, 2019Co-Authors: Sangeetha Iyer, Nina Diprimio, Graeme Preston, Jan Verheijen, Kausalya Murthy, Hillary Tsang, Zachary Parton, Eva Morava, Ethan O PerlsteinAbstract:ABSTRACT Phosphomannomutase 2 deficiency, or PMM2-CDG, is the most common congenital disorder of glycosylation and affects over 1000 patients globally. There are no approved drugs that treat the symptoms or root cause of PMM2-CDG. To identify clinically actionable compounds that boost human PMM2 enzyme function, we performed a multispecies drug repurposing screen using a novel worm model of PMM2-CDG, followed by PMM2 enzyme functional studies in PMM2-CDG patient fibroblasts. Drug repurposing candidates from this study, and drug repurposing candidates from a previously published study using yeast models of PMM2-CDG, were tested for their effect on human PMM2 enzyme activity in PMM2-CDG fibroblasts. Of the 20 repurposing candidates discovered in the worm-based phenotypic screen, 12 were plant-based polyphenols. Insights from structure–activity relationships revealed epalrestat, the only antidiabetic aldose reductase inhibitor approved for use in humans, as a first-in-class PMM2 enzyme activator. Epalrestat increased PMM2 enzymatic activity in four PMM2-CDG patient fibroblast lines with genotypes R141H/F119L, R141H/E139K, R141H/N216I and R141H/F183S. PMM2 enzyme activity gains ranged from 30% to 400% over baseline, depending on genotype. Pharmacological inhibition of aldose reductase by epalrestat may shunt glucose from the polyol pathway to glucose-1,6-bisphosphate, which is an endogenous stabilizer and coactivator of PMM2 homodimerization. Epalrestat is a safe, oral and brain penetrant drug that was approved 27 years ago in Japan to treat diabetic neuropathy in geriatric populations. We demonstrate that epalrestat is the first small molecule activator of PMM2 enzyme activity with the potential to treat peripheral neuropathy and correct the underlying enzyme deficiency in a majority of pediatric and adult PMM2-CDG patients.
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Renal involvement in PMM2-CDG, a mini-review
Molecular genetics and metabolism, 2017Co-Authors: Ruqaiah Altassan, Jaak Jaeken, David Cassiman, Peter Witters, Zubaida Saifudeen, Dulce Quelhas, Elena Levtchenko, Eva MoravaAbstract:Phosphomannomutase 2 deficiency (PMM2-CDG) is the most common N-linked glycosylation disorder. The majority of patients present with a multisystem phenotype, including central nervous system involvement, hepatopathy, gastrointestinal and cardiac symptoms, endocrine dysfunction and abnormal coagulation. Renal abnormalities including congenital malformations and altered renal function are part of the multisystem manifestations of congenital disorders of glycosylation. We reviewed the literature on 933 patients with molecularly and/or enzymatically confirmed PMM2 deficiency to evaluate the incidence of renal involvement in PMM2-CDG. Renal abnormalities were reported in 56 patients. Congenital abnormalities were present in 41 out of these 55. Cystic kidney and mild proteinuria were the most common findings. One of the most severe renal manifestations, congenital nephrotic syndrome, was detected in 6 children. Renal manifestations were not associated with the presence of specific PMM2 alleles. This review summarizes the reported renal abnormalities in PMM2-CDG and draws attention to the pathophysiological impact of abnormal glycosylation on kidney structure and function.
Gert Matthijs - One of the best experts on this subject based on the ideXlab platform.
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Long-term follow-up in PMM2-CDG: are we ready to start treatment trials?
Genetics in medicine : official journal of the American College of Medical Genetics, 2018Co-Authors: Peter Witters, Ruqaiah Altassan, Delphine Borgel, Tomas Honzik, Nathalie Seta, Eric Bauchart, Tiffany Pascreau, Arnaud Bruneel, Sandrine Vuillaumier, Gert MatthijsAbstract:PMM2-CDG is the most common congenital disorder of glycosylation (CDG), which presents with either a neurologic or multisystem phenotype. Little is known about the longitudinal evolution. We performed data analysis on PMM2-CDG patients’ clinical features according to the Nijmegen CDG severity score and laboratory data. Seventy-five patients (28 males) were followed up from 11.0 ± 6.91 years for an average of 7.4 ± 4.5 years. On a group level, there was no significant evolution in overall clinical severity. There was some improvement in mobility and communication, liver and endocrine function, and strabismus and eye movements. Educational achievement and thyroid function worsened in some patients. Overall, the current clinical function, the system-specific involvement, and the current clinical assessment remained unchanged. On follow-up there was improvement of biochemical variables with (near) normalization of activated partial thromboplastin time (aPTT), factor XI, protein C, antithrombin, thyroid stimulating hormone, and liver transaminases. PMM2-CDG patients show a spontaneous biochemical improvement and stable clinical course based on the Nijmegen CDG severity score. This information is crucial for the definition of endpoints in clinical trials.
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Characterization of two unusual truncating PMM2 mutations in two CDG-Ia patients
Molecular genetics and metabolism, 2007Co-Authors: Els Schollen, Paz Briones, Liesbeth Keldermans, Ron A. Wevers, François Foulquier, Amparo Chabas, Felix Sánchez-valverde, Maciej Adamowicz, Ewa Pronicka, Gert MatthijsAbstract:Congenital disorders of glycosylation type Ia (CDG-Ia) is a recessive metabolic disorder caused by mutations in the PMM2 gene and characterized by a defect in the synthesis of N-glycans. The clinical presentation ranges from very severe multi-organ failure to mild neurological problems. A plethora of PMM2 mutations has been described and the vast majority are missense mutations. This selection reflects the requirement of a minimal phosphomannomutase activity to be compatible with life. We describe the characterization of two unusual truncating mutations in two CDG-Ia patients. The first patient is compound heterozygous for the PMM2 mutation p.V231M (c.691G>A) and a deep intronic point mutation (c.639-15.479C>T). The latter variant activates a cryptic splice site which results in an in-frame insertion of a pseudoexon of 123 bp between exon 7 and 8. The second patient is compound heterozygous for the mutation p.V44A (c.131T>C) and an Alu retrotransposition mediated complex deletion of approximately 28 kb encompassing exon 8. These types of mutations have not been described before in CDG-Ia patients. Their detection stresses the importance to combine PMM2 mutation screening on genomic DNA with analysis of the transcripts and/or with the enzymatic analysis of the phosphomannomutase activity. Next to the exonic deletions, which already receive more attention than before, it is likely that deep intronic mutations represent an increasingly important category of mutations.
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Targeted disruption of the mouse phosphomannomutase 2 gene causes early embryonic lethality
Molecular and cellular biology, 2006Co-Authors: Christian Thiel, Gert Matthijs, Torben Lübke, Kurt Von Figura, Christian KornerAbstract:Mutations in the cytosolic enzyme phosphomannomutase 2 (PMM2), which catalyzes the conversion of mannose-6-phosphate to mannose-1-phosphate, cause the most common form of congenital disorders of glycosylation, termed CDG-Ia. It is an inherited multisystemic disease with severe neurological impairment. To study the pathophysiology of CDG-Ia and to investigate possible therapeutic approaches, we generated a mouse model for CDG-Ia by targeted disruption of the PMM2 gene. Heterozygous mutant mice appeared normal in development, gross anatomy, and fertility. In contrast, embryos homozygous for the PMM2-null allele were recovered in embryonic development at days 2.5 to 3.5. These results indicate that PMM2 is essential for early development of mice. Mating experiments of heterozygous mice with wild-type mice could further show that transmission of the female PMM2-null allele is impaired.
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Tissue distribution of the murine phosphomannomutases Pmm1 and PMM2 during brain development
The European journal of neuroscience, 2005Co-Authors: Kathy Cromphout, Jean-françois Collet, Liesbeth Keldermans, An Snellinx, S Grünewald, N De Geest, Raphael Sciot, E Vanschaftingen, Jacques Jaeken, Gert MatthijsAbstract:The most common type of the congenital disorders of glycosylation, CDG-Ia, is caused by mutations in the human PMM2 gene, reducing phosphomannomutase (PMM) activity. The PMM2 mutations mainly lead to neurological symptoms, while other tissues are only variably affected. Another phosphomannomutase, PMM1, is present at high levels in the brain. This raises the question why PMM1 does not compensate for the reduced PMM2 activity during CDG-Ia pathogenesis. We compared the expression profile of the murine Pmm1 and PMM2 mRNA and protein in prenatal and postnatal mouse brain at the histological level. We observed a considerable expression of both Pmms in different regions of the embryonic and adult mouse brain. Surprisingly, the expression patterns were largely overlapping. This data indicates that expression differences on the cellular and tissue level are an unlikely explanation for the absence of functional compensation. These results suggest that Pmm1 in vivo does not exert the phosphomannomutase-like activity seen in biochemical assays, but either acts on as yet unidentified specific substrates or fulfils entirely different functions.
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Identification and localization of two mouse phosphomannomutase genes, Pmm1 and PMM2.
Gene, 2001Co-Authors: Leen Heykants, Els Schollen, S Grünewald, Gert MatthijsAbstract:Abstract Phosphomannomutases catalyze the reversible conversion of mannose 6-phosphate to mannose 1-phosphate. In humans, two different isozymes have recently been identified, PMM1 and PMM2. We have previously shown that mutations in the PMM2 gene cause the most frequent type of the congenital disorders of glycosylation, CDG-Ia. Here, we present data on the two mouse orthologous genes, Pmm1 and PMM2. The chromosomal localization of the two mouse genes has been determined. We also present the gene structure and the exon-intron organization of Pmm1 and PMM2. Pmm1 maps to mouse chromosome 15, PMM2 to chromosome 16. These chromosomal regions are syntenic with regions on human chromosomes 22 and 16, respectively. The Pmm1 gene is composed of eight exons and spans approximately 9.5 kb. The genomic structure is extremely well conserved between the human and mouse gene. The PMM2 gene consists of eight exons and spans a larger genomic region (≈20 kb). An alignment of the human and mouse protein sequences confirms the conservation among this family of phosphomannomutases. The two mouse genes are expressed in many tissues, but the expression pattern is slightly different between Pmm1 and PMM2. The most striking difference is the high expression of Pmm1 in brain tissue, whereas PMM2 is only weakly expressed in this tissue.
Belén Pérez - One of the best experts on this subject based on the ideXlab platform.
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New and potential strategies for the treatment of PMM2-CDG.
Biochimica et biophysica acta. General subjects, 2020Co-Authors: Alejandra Gámez, Mercedes Serrano, Diana Gallego, Alicia Vilas, Belén PérezAbstract:Abstract Background Mutations in the PMM2 gene cause phosphomannomutase 2 deficiency (PMM2; MIM# 212065 ), which manifests as a congenital disorder of glycosylation (PMM2-CDG). Mutant PMM2 leads to the reduced conversion of Man-6-P to Man-1-P, which results in low concentrations of guanosine 5′-diphospho-D-mannose, a nucleotide-activated sugar essential for the construction of protein oligosaccharide chains. To date the only therapeutic options are preventive and symptomatic. Scope of review This review covers the latest advances in the search for a treatment for PMM2-CDG. Major conclusions Treatments based on increasing Man-1-P levels have been proposed, along with the administration of different mannose derivates, employing enzyme inhibitors or repurposed drugs to increase the synthesis of GDP-Man. A single repurposed drug that might alleviate a severe neurological symptom associated with the disorder is now in clinical use. Proof of concept also exists regarding the use of pharmacological chaperones and/or proteostatic regulators to increase the concentration of hypomorphic PMM2 mutant proteins. General significance The ongoing challenges facing the discovery of drugs to treat this orphan disease are discussed.
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PMM2-CDG caused by uniparental disomy: Case report and literature review.
JIMD reports, 2020Co-Authors: Laurien Vaes, Belén Pérez, George E. Tiller, Suzanne Boyer, Susan A. Berry, Kyriakie Sarafoglou, Eva MoravaAbstract:Background Phosphomannomutase 2 deficiency (PMM2-CDG) affects glycosylation pathways such as the N-glycosylation pathway, resulting in loss of function of multiple proteins. This disorder causes multisystem involvement with a high variability among patients. PMM2-CDG is an autosomal recessive disorder, which can be caused by inheriting two pathogenic variants, de novo mutations or uniparental disomy. Case presentation Our patient presented with multisystem symptoms at an early age including developmental delay, ataxia, and seizures. No diagnosis was obtained till the age of 31 years, when genetic testing was reinitiated. The patient was diagnosed with a complete maternal mixed hetero/isodisomy of chromosome 16, with a homozygous pathogenic PMM2 variant (p.Phe119Leu) causing PMM2-CDG.A literature review revealed eight cases of uniparental disomy as an underlying cause of CDG, four of which are PMM2-CDG. Conclusion Since the incidence of homozygosity for PMM2 variants is rare, we suggest further investigations for every homozygous PMM2-CDG patient where the segregation does not fit. These investigations include testing for UPD or a deletion in one of the two alleles, as this will have an impact on recurrence risk in genetic counseling.
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Longitudinal volumetric and 2D assessment of cerebellar atrophy in a large cohort of children with phosphomannomutase deficiency (PMM2-CDG).
Journal of inherited metabolic disease, 2017Co-Authors: Víctor De Diego, Celia Pérez-cerdá, Belén Pérez, Belén Pérez-dueñas, Daniel Cuadras, Rafael Artuch, Antonio F Martínez-monseny, Jordi Muchart, Raquel Montero, Andrea PorettiAbstract:We aim to delineate the progression of cerebellar atrophy (the primary neuroimaging finding) in children with phosphomannomutase-deficiency (PMM2-CDG) by analyzing longitudinal MRI studies and performing cerebellar volumetric analysis and a 2D cerebellar measurement. Statistical analysis was used to compare MRI measurements [midsagittal vermis relative diameter (MVRD) and volume] of children with PMM2-CDG and sex- and age-matched controls, and to determine the rate of progression of cerebellar atrophy at different ages. Fifty MRI studies of 33 PMM2-CDG patients were used for 2D evaluation, and 19 MRI studies were available for volumetric analysis. Results from a linear regression model showed that patients have a significantly lower MVRD and cerebellar volume compared to controls (p < 0.001 and p < 0.001 respectively). There was a significant negative correlation between age and MVRD for patients (p = 0.014). The rate of cerebellar atrophy measured by the loss of MVRD and cerebellar volume per year was higher at early ages (r = -0.578, p = 0.012 and r = -0.323, p = 0.48 respectively), particularly in patients under 11 years (p = 0.004). There was a significant positive correlation between MVRD and cerebellar volume in PMM2-CDG patients (r = 0.669, p = 0.001). Our study quantifies a progression of cerebellar atrophy in PMM2-CDG patients, particularly during the first decade of life, and suggests a simple and reliable measure, the MVRD, to monitor cerebellar atrophy. Quantitative measurement of MVRD and cerebellar volume are essential for correlation with phenotype and outcome, natural follow-up, and monitoring in view of potential therapies in children with PMM2-CDG.
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Pharmacological Chaperoning: A Potential Treatment for PMM2-CDG.
Human mutation, 2016Co-Authors: Patricia Yuste-checa, Alejandra Gámez, Sandra Brasil, Lourdes R. Desviat, Magdalena Ugarte, Celia Pérez-cerdá, Jarl Underhaug, Aurora Martinez, Belén PérezAbstract:The congenital disorder of glycosylation (CDG) due to phosphomannomutase 2 deficiency (PMM2-CDG), the most common N-glycosylation disorder, is a multisystem disease for which no effective treatment is available. The recent functional characterization of disease-causing mutations described in patients with PMM2-CDG led to the idea of a therapeutic strategy involving pharmacological chaperones (PC) to rescue PMM2 loss-of-function mutations. The present work describes the high-throughput screening, by differential scanning fluorimetry, of 10,000 low-molecular-weight compounds from a commercial library, to search for possible PCs for the enzyme PMM2. This exercise identified eight compounds that increased the thermal stability of PMM2. Of these, four compounds functioned as potential PCs that significantly increased the stability of several destabilizing and oligomerization mutants and also increased PMM activity in a disease model of cells overexpressing PMM2 mutations. Structural analysis revealed one of these compounds to provide an excellent starting point for chemical optimization since it passed tests based on a number of pharmacochemical quality filters. The present results provide the first proof-of-concept of a possible treatment for PMM2-CDG and describe a promising chemical structure as a starting point for the development of new therapeutic agents for this severe orphan disease.
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The Effects of PMM2-CDG-Causing Mutations on the Folding, Activity, and Stability of the PMM2 Protein.
Human mutation, 2015Co-Authors: Patricia Yuste-checa, Alejandra Gámez, Sandra Brasil, Lourdes R. Desviat, Magdalena Ugarte, Celia Pérez-cerdá, Belén PérezAbstract:Congenital disorder of glycosylation type Ia (PMM2-CDG), the most common form of CDG, is caused by mutations in the PMM2 gene that reduce phosphomannomutase 2 (PMM2) activity. No curative treatment is available. The present work describes the functional analysis of nine human PMM2 mutant proteins frequently found in PMM2-CDG patients and also two murine PMM2 mutations carried by the unique PMM2-CDG mouse model described to overcome embryonic lethality. The effects of the mutations on PMM2/PMM2 stability, oligomerization, and enzyme activity were explored in an optimized bacterial system. The mutant proteins were associated with an enzymatic activity of up to 47.3% as compared with wild type (WT). Stability analysis performed using differential scanning fluorimetry and a bacterial transcription–translation-coupled system allowed the identification of several destabilizing mutations (p.V44A, p.D65Y, p.R123Q, p.R141H, p.R162W, p.F207S, p.T237M, p.C241S). Exclusion chromatography identified one mutation, p.P113L, that affected dimer interaction. Expression analysis of the p.V44A, p.D65Y, p.R162W, and p.T237M mutations in a eukaryotic expression system under permissive folding conditions showed the possibility of recovering their associated PMM2 activity. Together, the results suggest that some loss-of-function mutations detected in PMM2-CDG patients could be destabilizing, and therefore PMM2 activity could be, in certain cases, rescuable via the use of synergetic proteostasis modulators and/or chaperones.
Hudson H. Freeze - One of the best experts on this subject based on the ideXlab platform.
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Spontaneous improvement of carbohydrate-deficient transferrin in PMM2-CDG without mannose observed in CDG natural history study.
Orphanet journal of rare diseases, 2021Co-Authors: Peter Witters, Hudson H. Freeze, Andrew C. Edmondson, Christina Lam, Christin Johnsen, Marc C. Patterson, Kimiyo Raymond, Eva MoravaAbstract:A recent report on long-term dietary mannose supplementation in phosphomannomutase 2 deficiency (PMM2-CDG) claimed improved glycosylation and called for double-blind randomized study of the dietary supplement in PMM2-CDG patients. A lack of efficacy of short-term mannose supplementation in multiple prior reports challenge this study's conclusions. Additionally, some CDG types have previously been reported to demonstrate spontaneous improvement in glycosylated biomarkers, including transferrin. We have likewise observed improvements in transferrin glycosylation without mannose supplementation. This observation questions the reliability of transferrin as a therapeutic outcome measure in clinical trials for PMM2-CDG. We are concerned that renewed focus on mannose therapy in PMM2-CDG will detract from clinical trials of more promising therapies. Approaches to increase efficiency of clinical trials and ultimately improve patients' lives requires prospective natural history studies and identification of reliable biomarkers linked to clinical outcomes in CDG. Collaborations with patients and families are essential to identifying meaningful study outcomes.
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Insufficient ER-stress response causes selective mouse cerebellar granule cell degeneration resembling that seen in congenital disorders of glycosylation
Molecular brain, 2013Co-Authors: Liangwu Sun, Hudson H. Freeze, Yingjun Zhao, Kun Zhou, Yun-wu ZhangAbstract:Background Congenital disorders of glycosylation (CDGs) are inherited diseases caused by glycosylation defects. Incorrectly glycosylated proteins induce protein misfolding and endoplasmic reticulum (ER) stress. The most common form of CDG, PMM2-CDG, is caused by deficiency in the cytosolic enzyme phosphomannomutase 2 (PMM2). Patients with PMM2-CDG exhibit a significantly reduced number of cerebellar Purkinje cells and granule cells. The molecular mechanism underlying the specific cerebellar neurodegeneration in PMM2-CDG, however, remains elusive.
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A Zebrafish Model Of PMM2-CDG Reveals Altered Neurogenesis And A Substrate-Accumulation Mechanism For N-Linked Glycosylation Deficiency
Molecular biology of the cell, 2012Co-Authors: Abigail Cline, Vandana Sharma, Ningguo Gao, Heather Flanagan-steet, Sabrina Rosa, Roberto Sonon, Parastoo Azadi, Kirsten C. Sadler, Hudson H. Freeze, Mark A. LehrmanAbstract:Congenital disorder of glycosylation (PMM2-CDG) results from mutations in PMM2, which encodes the phosphomannomutase (Pmm) that converts mannose-6-phosphate (M6P) to mannose-1-phosphate (M1P). Patients have wide-spectrum clinical abnormalities associated with impaired protein N-glycosylation. Although it has been widely proposed that PMM2 deficiency depletes M1P, a precursor of GDP-mannose, and consequently suppresses lipid-linked oligosaccharide (LLO) levels needed for N-glycosylation, these deficiencies have not been demonstrated in patients or any animal model. Here we report a morpholino-based PMM2-CDG model in zebrafish. Morphant embryos had developmental abnormalities consistent with PMM2-CDG patients, including craniofacial defects and impaired motility associated with altered motor neurogenesis within the spinal cord. Significantly, global N-linked glycosylation and LLO levels were reduced in PMM2 morphants. Although M1P and GDP-mannose were below reliable detection/quantification limits, PMM2 depletion unexpectedly caused accumulation of M6P, shown earlier to promote LLO cleavage in vitro. In PMM2 morphants, the free glycan by-products of LLO cleavage increased nearly twofold. Suppression of the M6P-synthesizing enzyme mannose phosphate isomerase within the PMM2 background normalized M6P levels and certain aspects of the craniofacial phenotype and abrogated PMM2-dependent LLO cleavage. In summary, we report the first zebrafish model of PMM2-CDG and uncover novel cellular insights not possible with other systems, including an M6P accumulation mechanism for underglycosylation.
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Functional significance of PMM2 mutations in mildly affected patients with congenital disorders of glycosylation Ia
Genetics in Medicine, 2001Co-Authors: Vibeke Westphal, Sandra Peterson, Marc Patterson, Anne Tournay, Andrea Blumenthal, Eileen P Treacy, Hudson H. FreezeAbstract:Purpose: Congenital disorders of glycosylation (CDG) result from mutations in N-glycan biosynthesis. Mutations in phosphomannomutase ( PMM2 ) cause CDG-Ia. Here, we report four clinically mild patients and their mutations in PMM2. Methods: Analysis of the PMM2 cDNA and gene revealed the mutations affecting the glycosylation efficiency. Results: The patients have 30% to 50% normal PMM activity in fibroblasts due to different mutations in PMM2 , and we studied the effect of each mutation on the PMM activity in a Saccharomyces cerevisiae expression system. Conclusions: Each patient carried a severe mutation that decreased the PMM activity to less than 10% as well as a relatively mild mutation. A new mutation, deletion of base 24, changed the reading frame. The C9Y, C241S, and L32R mutations showed 27% to 45% activity when expressed in the eukaryotic expression system, and the more severe D148N was shown to be thermolabile.
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Mutations in PMM2 that cause congenital disorders of glycosylation, type Ia (CDG-Ia).
Human mutation, 2000Co-Authors: Gert Matthijs, Els Schollen, Susanne Kjaergaard, Marianne Schwartz, Hudson H. Freeze, Anna Erlandson, Tommy Martinsson, Cecilia Bjursell, Faiqa Imtiaz, Nathalie SetaAbstract:The PMM2 gene, which is defective in CDG-Ia, was cloned three years ago [Matthijs ct al., 1997b]. Several publications list PMM2 mutations [Matthijs et al., 1997b, 1998; Kjaergaard et al., 1998, 1999; Bjursell et al., 1998, 2000; Imtiaz et al., 2000] and a few mutations have appeared in case reports or abstracts [Crosby et al., 1999; Kondo et al., 1999; Krasnewich ct al,, 1999; Mizugishi et al,, 1999; Vuillaumier-Barrot ct al., 1999, 2000b]. However, the number of molecularly characterized cases is steadily increasing and many new mutations may never make it to the literature. Therefore, we decided to collate data from six research and diagnostic laboratories that have committed themselves to a systematic search for PMM2 mutations. In total we list 58 different mutations found in 249 patients from 23 countries. We have also collected demographic data and registered the number of deceased patients. The documentation of the genotype-phenotype correlation is certainly valuable, but is out of the scope of this molecular update. The list of mutations will also be available online (URL: http://www.kuleuven.ac.be/med/cdg) and investigators are invited to submit new data to this PMM2 mutation database. Hum Mutat 16:386-394, 2000. (C) 2000 Wiley-Liss, Inc.
Christian Korner - One of the best experts on this subject based on the ideXlab platform.
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successful prenatal mannose treatment for congenital disorder of glycosylation ia in mice
Nature Medicine, 2012Co-Authors: Anette Schneider, Jan Rindermann, Charles Derossi, Diana Popovici, Christian T Thiel, Hermann Josef Gröne, Georg F Hoffmann, Christian KornerAbstract:Congenital disorder of glycosylation-Ia in humans is a multisystemic disease marked by severe neurological deficits and results from deficient glycoprotein processing during development. Christian Korner and his colleagues now show that orally supplying mannose to pregnant dams in a mouse model of the disease is sufficient to ameliorate disease symptoms and early lethality, suggesting a possible therapy to treat this devastating condition. Congenital disorder of glycosylation-Ia (CDG-Ia, also known as PMM2-CDG) is caused by mutations in the gene that encodes phosphomannomutase 2 (PMM2, EC 5.4.2.8) leading to a multisystemic disease with severe psychomotor and mental retardation. In a hypomorphic PMM2 mouse model, we were able to overcome embryonic lethality by feeding mannose to pregnant dams. The results underline the essential role of glycosylation in embryonic development and may open new treatment options for this disease.
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Successful prenatal mannose treatment for congenital disorder of glycosylation-Ia in mice.
Nature medicine, 2011Co-Authors: Anette Schneider, Jan Rindermann, Charles Derossi, Diana Popovici, Hermann Josef Gröne, Georg F Hoffmann, Christian Thiel, Christian KornerAbstract:Congenital disorder of glycosylation-Ia (CDG-Ia, also known as PMM2-CDG) is caused by mutations in the gene that encodes phosphomannomutase 2 (PMM2, EC 5.4.2.8) leading to a multisystemic disease with severe psychomotor and mental retardation. In a hypomorphic PMM2 mouse model, we were able to overcome embryonic lethality by feeding mannose to pregnant dams. The results underline the essential role of glycosylation in embryonic development and may open new treatment options for this disease.
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Targeted disruption of the mouse phosphomannomutase 2 gene causes early embryonic lethality
Molecular and cellular biology, 2006Co-Authors: Christian Thiel, Gert Matthijs, Torben Lübke, Kurt Von Figura, Christian KornerAbstract:Mutations in the cytosolic enzyme phosphomannomutase 2 (PMM2), which catalyzes the conversion of mannose-6-phosphate to mannose-1-phosphate, cause the most common form of congenital disorders of glycosylation, termed CDG-Ia. It is an inherited multisystemic disease with severe neurological impairment. To study the pathophysiology of CDG-Ia and to investigate possible therapeutic approaches, we generated a mouse model for CDG-Ia by targeted disruption of the PMM2 gene. Heterozygous mutant mice appeared normal in development, gross anatomy, and fertility. In contrast, embryos homozygous for the PMM2-null allele were recovered in embryonic development at days 2.5 to 3.5. These results indicate that PMM2 is essential for early development of mice. Mating experiments of heterozygous mice with wild-type mice could further show that transmission of the female PMM2-null allele is impaired.